Glimepiride-teva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLIMEPIRIDE-TEVA (GLIMEPIRIDE-TEVA)

Composition:

Active substance: glimepiride;

1 tablet contains 2 mg, 3 mg, or 4 mg of glimepiride;

Excipients:

Tablets of 2 mg – lactose monohydrate, sodium starch glycolate, povidone, microcrystalline cellulose, magnesium stearate, iron oxide yellow (E 172), indigo carmine aluminium lake (E 132);

Tablets of 3 mg – lactose monohydrate, sodium starch glycolate, povidone, microcrystalline cellulose, magnesium stearate, iron oxide yellow (E 172);

Tablets of 4 mg – lactose monohydrate, sodium starch glycolate, povidone, microcrystalline cellulose, magnesium stearate, indigo carmine aluminium lake (E 132).

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets of 2 mg – round green tablets with speckles, with a break line on each side. On one side of the tablet – imprint "9" on one side and "3" on the other side of the break line. On the other side of the tablet – imprint "72" on one side and "55" on the other side of the break line.

Tablets of 3 mg – round light yellow or yellow tablets, with a break line on each side. On one side of the tablet – imprint "G" on one side and "3" on the other side of the break line.

Tablets of 4 mg – round blue tablets with speckles, with a break line on each side. On one side of the tablet – imprint "9" on one side and "3" on the other side of the break line. On the other side of the tablet – imprint "72" on one side and "56" on the other side of the break line.

Pharmacotherapeutic group. Antihyperglycemic agents, excluding insulin. Sulfonamides, urea derivatives. ATC code A10B B12.

Pharmacological properties.

Pharmacodynamics.

Glimepiride is an orally active hypoglycemic agent belonging to the sulfonylurea group. It can be used in insulin-independent diabetes mellitus.

Glimepiride acts primarily by stimulating the release of insulin from pancreatic beta cells.

As with other sulfonylurea agents, this effect is based on increasing the sensitivity of pancreatic beta cells to the physiological stimulation by glucose. In addition, glimepiride exerts a pronounced extrapancreatic effect, which is also characteristic of other sulfonylurea agents.

Insulin release. Sulfonylurea agents regulate insulin secretion by closing ATP-sensitive potassium channels in the beta-cell membrane. Closure of potassium channels induces depolarization of the beta cell, leading to the opening of calcium channels and increased calcium influx into the cell, resulting in insulin release via exocytosis.

Glimepiride binds rapidly and specifically to a protein in the beta-cell membrane associated with the ATP-sensitive potassium channel; however, its binding site differs from the conventional binding site of sulfonylurea agents.

Extrapancreatic activity. Extrapancreatic effects include, for example, improved insulin sensitivity in peripheral tissues and reduced hepatic insulin clearance.

Utilization of blood glucose by peripheral tissues (muscle and adipose tissue) occurs via specific transport proteins located in the cell membrane. Glucose transport into these tissues is limited by the rate of glucose utilization. Glimepiride rapidly increases the number of active glucose-transporting molecules in the plasma membranes of muscle and adipose cells, thereby stimulating glucose uptake.

Glimepiride increases the activity of glycosylphosphatidylinositol-specific phospholipase C, which in isolated muscle and fat cells may correlate with drug-induced lipogenesis and glycogenesis.

Glimepiride inhibits glucose production in the liver by increasing intracellular concentrations of fructose-2,6-bisphosphate, which suppresses gluconeogenesis.

General characteristics. In healthy volunteers, the minimal effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical stress, i.e., reduced insulin secretion, is preserved under the influence of glimepiride.

No significant difference in glimepiride action was observed between administration 30 minutes before or immediately before a meal. In patients with diabetes, adequate metabolic control over 24 hours can be achieved with once-daily dosing.

Although the hydroxylated metabolite causes a slight but statistically significant reduction in blood glucose levels in healthy volunteers, this represents only a minor component of the overall drug effect.

Combination with metformin. One study demonstrated improved metabolic control with combination therapy using glimepiride compared to metformin monotherapy in patients whose diabetes was not adequately controlled with maximum doses of metformin.

Combination with insulin. Data on the use of glimepiride in combination with insulin are limited. In patients whose diabetes is not adequately controlled with maximum doses of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved metabolic control comparable to insulin monotherapy; however, with combination therapy, a lower average insulin dose was required.

Special patient populations. Children, including adolescents. In a 24-week active-controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2000 mg daily), 285 children (aged 8–17 years) with type 2 diabetes were enrolled.

Both glimepiride and metformin led to a statistically significant reduction in HbA1c compared to baseline (glimepiride – 0.95 (SE 0.41); metformin – 1.39 (SE 0.40)). However, glimepiride did not demonstrate superior efficacy compared to metformin in terms of mean HbA1c change from baseline. The difference between the two treatments was 0.44% in favor of metformin. The upper limit (1.05) of the 95% confidence interval for this difference exceeded the 0.3% non-inferiority margin.

No new safety concerns were identified with glimepiride treatment in children compared to adult patients with type 2 diabetes. Long-term efficacy and safety data in children are lacking.

Pharmacokinetics.

Absorption. After oral administration, glimepiride has 100% bioavailability. Food intake does not significantly affect absorption but slightly slows the rate of absorption. Maximum plasma concentration (Cmax) is reached approximately 2.5 hours after oral administration (mean value is 0.3 µg/mL with repeated administration of a 4 mg daily dose). There is a linear relationship between dose and Cmax, as well as between dose and AUC (area under the concentration-time curve).

Distribution. Glimepiride has a low volume of distribution (approximately 8.8 L), roughly equivalent to the distribution volume of albumin, a high degree of plasma protein binding (>99%), and low clearance (approximately 48 mL/min).

In animals, glimepiride is excreted into breast milk. Glimepiride crosses the placenta. Penetration across the blood-brain barrier is low.

Metabolism and elimination. The mean terminal half-life at plasma concentrations corresponding to repeated dosing regimens is approximately 5–8 hours. A slight increase in half-life was observed after administration of high doses.

After a single dose of radiolabeled glimepiride, 58% of the radioactivity was recovered in urine and 35% in feces. Unchanged drug was not detected in urine. Two metabolites were identified in urine and feces, most likely formed via hepatic metabolism (main enzyme CYP2C9), one being a hydroxy derivative and the other a carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3–6 hours and 5–6 hours, respectively.

Comparison of pharmacokinetics after single and repeated once-daily dosing revealed no significant differences. Inter-individual variability was very low. No clinically relevant accumulation was observed.

Special patient populations. Pharmacokinetic parameters in men and women, as well as in young and elderly individuals (over 65 years), were similar. In patients with reduced creatinine clearance, a trend toward increased glimepiride clearance and decreased mean plasma concentration was observed, likely due to faster elimination resulting from reduced protein binding. Renal excretion of both metabolites was impaired. Overall, increased risk of drug accumulation is not expected in these patients.

Pharmacokinetic parameters in 5 non-diabetic patients who underwent biliary tract surgery were similar to those in healthy volunteers.

Children, including adolescents. A study evaluating pharmacokinetics, safety, and tolerability after a single 1 mg dose of glimepiride administered with food in 30 children (4 aged 10–12 years and 26 aged 12–17 years) with type 2 diabetes demonstrated that mean AUC(0-last), Cmax, and t1/2 values were similar to those in adults.

Preclinical safety data. Effects observed during preclinical studies occurred at exposure levels substantially exceeding maximum human exposure levels, indicating limited clinical relevance, or were due to the pharmacodynamic action of the drug (hypoglycemia). These findings were obtained within traditional safety pharmacology studies, repeated-dose toxicity studies, genotoxicity tests, carcinogenic potential, and reproductive toxicity studies. Adverse effects identified in the latter (including studies on embryotoxicity, teratogenicity, and developmental toxicity) were considered consequences of drug-induced hypoglycemic effects in pregnant females and offspring.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus in adults when blood glucose levels cannot be controlled by diet, physical activity, and weight reduction alone.

Contraindications.

• Hypersensitivity to glimepiride or to any excipient of the medicinal product, to other sulfonylurea derivatives, or to other sulfonamide-containing drugs;
• Insulin-dependent diabetes mellitus;
• Diabetic coma;
• Diabetic ketoacidosis;
• Severe renal or hepatic impairment.

In cases of severe renal or hepatic impairment, patients must be switched to insulin therapy.

Interaction with other medicinal products and other forms of interaction.

The concomitant use of glimepiride with certain other medicinal products may lead to undesirable increases or decreases in the hypoglycemic effect of glimepiride. Therefore, other medicinal products should be used only as directed by a physician.

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). It is known that its metabolism may be affected by concomitant administration of inducers (e.g., rifampicin) or inhibitors of CYP2C9 (e.g., fluconazole).

In vivo studies have shown that the AUC of glimepiride approximately doubles when fluconazole (one of the most potent CYP2C9 inhibitors) is administered concomitantly.

The following types of interactions are based on clinical experience with glimepiride and other sulfonylurea derivatives.

Hypoglycemia due to enhanced hypoglycemic effect may occur when glimepiride is taken concomitantly with the following agents: phenylbutazone, azapropazone, and oxyphenbutazone, insulin and oral antidiabetic agents (such as metformin), salicylates and p-aminosalicylic acid, anabolic steroids and androgens, chloramphenicol, certain long-acting sulfonamides, tetracyclines, quinolone antibiotics and clarithromycin, coumarin anticoagulants, fenfluramine, disopyramide, fibrates, ACE inhibitors, fluoxetine, monoamine oxidase (MAO) inhibitors, allopurinol, probenecid, sulfinpyrazone, sympatholytics, cyclo-, tro-, and ifosfamide, miconazole, fluconazole, pentoxifylline (high doses administered parenterally), tritucqualine.

The hypoglycemic effect of glimepiride may be reduced, leading to deterioration in glycemic control, when glimepiride is taken concomitantly with the following medicinal products: estrogens and progestogens, diuretics, thiazide diuretics, thyroid-stimulating agents, glucocorticoids, phenothiazine derivatives, chlorpromazine, epinephrine and sympathomimetics, nicotinic acid (high doses) and nicotinic acid derivatives, laxatives (with prolonged use), phenytoin, diazoxide, glucagon, barbiturates and rifampicin, acetazolamide.

H2-receptor antagonists, beta-blockers, clonidine, and reserpine may either potentiate or reduce the hypoglycemic effect.

Under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of adrenergic counter-regulation during hypoglycemia may be diminished or absent.

Alcohol consumption may unpredictably enhance or weaken the hypoglycemic effect of glimepiride.

Glimepiride may potentiate or weaken the effect of coumarin derivatives.

Colesevelam binds to glimepiride and reduces its absorption from the gastrointestinal tract. No interactions were observed when glimepiride was administered at least 4 hours prior to colesevelam. Therefore, glimepiride should be taken at least 4 hours before colesevelam administration.

Special precautions for use.

Glimipiride-Teva should be taken immediately before or during a meal.

If a patient eats irregularly or completely forgets to eat, treatment with this medication may lead to hypoglycemia. Possible symptoms of hypoglycemia include headache, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, increased motor activity, aggressiveness, impaired concentration, anxiety, slowed reaction time, depressive mood, confusion, impaired consciousness, speech and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, seizures, somnolence, and loss of consciousness up to coma, shallow breathing, and bradycardia.

Additionally, symptoms of adrenergic counter-regulation may occur, such as sweating, cold and clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, angina pectoris, and cardiac arrhythmias.

The clinical picture of a severe hypoglycemic attack may resemble that of a stroke. Hypoglycemic symptoms can almost always be rapidly relieved by immediate intake of carbohydrates (sugar). Artificial sweeteners are ineffective.

Based on experience with other sulfonylurea derivatives, even after initial successful correction of hypoglycemia, it may recur.

Severe or prolonged hypoglycemia, which is only temporarily controlled by usual amounts of sugar, requires immediate treatment and sometimes hospitalization.

Factors predisposing to hypoglycemia:

• Patient's unwillingness or (more commonly in elderly patients) inability to cooperate with the physician;
• Inadequate food intake, irregular eating, skipping meals, or fasting periods;
• Dietary imbalances;
• Mismatch between physical exertion and carbohydrate intake;
• Alcohol consumption, especially in combination with skipped meals;
• Impaired renal function;
• Severe impairment of liver function;
• Glimipiride overdose;
• Certain decompensated endocrine disorders affecting carbohydrate metabolism or hypoglycemia counter-regulation (e.g., some thyroid disorders, hypopituitarism, or adrenal insufficiency);
• Concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Treatment with Glimipiride-Teva requires regular monitoring of blood and urine glucose levels. Additionally, measurement of glycated hemoglobin in blood is recommended.

During treatment, liver function tests and hematological parameters (especially white blood cell and platelet counts) should also be monitored regularly.

In stressful situations (e.g., trauma, unplanned surgery, infections with fever), temporary transition to insulin therapy may be indicated.

There is no experience with the use of glimipiride in patients with severe hepatic impairment or in patients on dialysis. Patients with severe renal or hepatic impairment should be switched to insulin therapy.

Administration of sulfonylurea drugs to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may lead to hemolytic anemia. Since glimipiride belongs to the class of sulfonylurea derivatives, it should be used with caution in patients with G6PD deficiency. Consideration should be given to switching such patients to alternative therapies with agents that are not sulfonylurea derivatives.

Excipients

Lactose. Glimipiride-Teva contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy

Risk associated with diabetes. Abnormal blood glucose levels during pregnancy may increase the risk of congenital malformations and perinatal mortality. Therefore, careful blood glucose monitoring of the pregnant woman is essential to avoid teratogenic risk.

Pregnant women with diabetes should be switched to insulin therapy. Women with diabetes should inform their physician about planned pregnancy to adjust treatment and switch to insulin.

Risk associated with glimipiride. There are insufficient data on the use of glimipiride during pregnancy. Animal studies have shown reproductive toxicity, likely due to the pharmacological effect (hypoglycemia) of glimipiride.

Therefore, glimipiride must not be used at any time during pregnancy.

In cases of planned pregnancy or if pregnancy occurs during treatment with glimipiride, therapy should be switched to insulin as soon as possible.

Breastfeeding period

It is unknown whether glimipiride is excreted in human breast milk. In rats, glimipiride is excreted in breast milk. Since other sulfonylurea derivatives are excreted in breast milk and considering the risk of hypoglycemia in breastfed infants, glimipiride is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted.

A patient's ability to concentrate and react quickly may be impaired due to hypoglycemia or hyperglycemia, or due to visual disturbances. This may pose a risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery).

Patients should be advised to take precautions to prevent hypoglycemia while driving. This is especially important for individuals who poorly or not at all recognize early warning signs of hypoglycemia, and for those who experience frequent hypoglycemic episodes. Serious consideration should be given to whether driving or operating machinery is appropriate under such circumstances.

Method of Administration and Dosage.

The medication is intended for oral administration.

Proper diabetes management is based on an appropriate diet, regular physical activity, and regular blood and urine testing. Medications cannot ensure adequate glycemic control if the patient does not adhere to the recommended diet.

The dosage of Glimepiride-Teva is determined based on blood and urine glucose measurements.

The initial dose is 1 mg (1/2 tablet of 2 mg) of glimepiride per day. If this dose achieves adequate glucose control, it should be maintained for ongoing treatment.

If satisfactory glucose control is not achieved, the dose should be gradually increased based on glycemic monitoring, with intervals of approximately 1–2 weeks between dose increments, up to 2, 3, or 4 mg of glimepiride per day. Different dosage strengths of the medication are available for various treatment regimens.

Doses exceeding 4 mg per day provide additional benefit only in exceptional cases. The maximum recommended daily dose of glimepiride is 6 mg.

If adequate glucose control is not achieved with the maximum daily dose of metformin, concomitant therapy with glimepiride may be initiated.

When maintaining the metformin dose, glimepiride therapy should be initiated at a low dose, which can then be gradually increased according to the desired level of metabolic control up to the maximum daily dose. Combination therapy should be initiated under close medical supervision.

If adequate glycemic control is not achieved with the maximum daily dose of glimepiride, concomitant insulin therapy may be initiated if necessary. When maintaining the glimepiride dose, insulin therapy should be started at a low dose, which can then be gradually increased depending on the desired level of metabolic control. Combination therapy should be initiated under close medical supervision.

Typically, a single daily dose of glimepiride is sufficient. It is recommended to take the dose shortly before or during a main meal, such as breakfast, or, if breakfast is not consumed, shortly before or during the first main meal of the day.

If a patient misses a dose, the next dose should not be doubled.

Tablets should be swallowed whole with liquid.

If a patient experiences a hypoglycemic reaction after daily intake of 1 mg of the medication, this indicates that glucose levels in this patient may be controlled by diet alone.

Improved diabetes control is associated with increased insulin sensitivity; therefore, during treatment, the requirement for glimepiride may decrease. To avoid hypoglycemia, the dose should be timely reduced or the medication discontinued. Dose adjustments may also be necessary due to changes in body weight, lifestyle, or other factors that increase the risk of hypo- or hyperglycemia.

Switching Patients from Other Oral Hypoglycemic Agents to Glimepiride

Such a switch is generally possible. When switching to Glimepiride-Teva, the dose and half-life of the previously used medication should be taken into account. In some cases, especially when using antidiabetic agents with a long half-life (e.g., chlorpropamide), the half-life should be considered over several days to minimize the risk of hypoglycemic reactions due to additive effects. The recommended initial dose is 1 mg of glimepiride per day. The dose can be gradually increased according to the patient's response, as described above.

Switching Patients from Insulin to Glimepiride

In exceptional cases, switching to glimepiride may be indicated for patients with type 2 diabetes who have been treated with insulin. Such a switch should be performed under close medical supervision.

Children

Currently, there is a lack of evidence-based data on the use of glimepiride in patients under 8 years of age. Limited data exist on the use of glimepiride as monotherapy in children aged 8 to 17 years (see sections "Pharmacodynamics" and "Pharmacokinetics"). Available data on the safety and efficacy of the medication in children are insufficient; therefore, its use is not recommended in this patient population.

Overdose

Overdose may lead to hypoglycemia lasting from 12 to 72 hours, which may recur after initial improvement. Symptoms may appear up to 24 hours after administration. Typically, such patients require clinical observation. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia is usually accompanied by neurological symptoms such as tremor, restlessness, visual disturbances, coordination disorders, drowsiness, coma, and seizures.

Treatment of overdose primarily involves preventing drug absorption by inducing vomiting, followed by administration of water or lemonade with activated charcoal (adsorbent) and sodium sulfate (laxative). If a large amount of glimepiride has been ingested, gastric lavage is indicated, followed by administration of activated charcoal and sodium sulfate. In cases of severe overdose, hospitalization in an intensive care unit is indicated. Glucose administration should be initiated as soon as possible. If necessary, a bolus intravenous injection of 50 ml of 50% glucose should be given, followed by infusion of 10% glucose solution, with careful monitoring of blood glucose levels. Further treatment is symptomatic.

When treating hypoglycemia caused by accidental glimepiride ingestion in infants and young children, the glucose dose must be carefully adjusted to avoid dangerous hyperglycemia, and blood glucose levels should be closely monitored.

Adverse Reactions

Based on experience with glimepiride and other sulfonylurea derivatives, the following adverse reactions have been reported, listed by organ system in decreasing order of frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Blood and Lymphatic System Disorders

Rare: thrombocytopenia, leukopenia, erythrocytopenia, granulocytopenia, agranulocytosis, hemolytic anemia, and pancytopenia. These effects usually resolve upon discontinuation of treatment.

Frequency not known: severe thrombocytopenia with platelet count below 10,000/μL and thrombocytopenic purpura.

Immune System Disorders

Very rare: leukocytoclastic vasculitis, mild hypersensitivity reactions that may progress to severe reactions with dyspnea, hypotension, and sometimes shock.

Frequency not known: possible cross-allergy with sulfonylurea derivatives, sulfonamides, or related substances.

Metabolic and Nutritional Disorders

Rare: hypoglycemia.

Such hypoglycemic reactions typically occur immediately, may be severe, and are not always easily corrected. The occurrence of such reactions, as with other hypoglycemic agents, depends on individual factors such as dietary habits and drug dosage (see section "Special Warnings and Precautions for Use" for details).

Eye Disorders

Frequency not known: transient visual disturbances may occur, especially at the beginning of treatment, due to changes in blood glucose levels.

Gastrointestinal Disorders

Very rare: nausea, vomiting, diarrhea, abdominal distension, abdominal discomfort, and abdominal pain, which rarely necessitate discontinuation of treatment.

Hepatobiliary Disorders

Very rare: liver function abnormalities (e.g., with cholestasis or jaundice), hepatitis, and hepatic failure.

Frequency not known: elevated liver enzymes.

Skin and Subcutaneous Tissue Disorders

Frequency not known: hypersensitivity reactions may occur, including pruritus, rash, urticaria, and photosensitivity.

Laboratory Findings

Very rare: decreased serum sodium levels.

Reporting Suspected Adverse Reactions

Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report all suspected adverse reactions through national reporting systems.

Shelf Life. 2 years.

Storage Conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 tablets per blister, 3 blisters per cardboard box.

Prescription Category. Prescription only.

Manufacturer.

1. Teva Pharmaceutical Industries Ltd.
2. AT Pharma Plant Teva.

Manufacturer's Address and Place of Business.

1. 18 Eli Hurvitz Street, Industrial Zone, Kfar-Saba, Israel.
2. Unit 1; Pállagi Street 13, H-4042 Debrecen, Hungary.